EP0219225B1 - Verfahren zur Herstellung von Ranitidin oder Säureadditionssalze davon und Zwischenprodukte für diese Herstellung - Google Patents

Verfahren zur Herstellung von Ranitidin oder Säureadditionssalze davon und Zwischenprodukte für diese Herstellung Download PDF

Info

Publication number
EP0219225B1
EP0219225B1 EP86306998A EP86306998A EP0219225B1 EP 0219225 B1 EP0219225 B1 EP 0219225B1 EP 86306998 A EP86306998 A EP 86306998A EP 86306998 A EP86306998 A EP 86306998A EP 0219225 B1 EP0219225 B1 EP 0219225B1
Authority
EP
European Patent Office
Prior art keywords
methyl
ranitidine
preparation
mmol
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP86306998A
Other languages
English (en)
French (fr)
Other versions
EP0219225A1 (de
Inventor
Borge Alhede
Finn Priess Clausen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AS
Original Assignee
GEA Farmaceutisk Fabrik AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GEA Farmaceutisk Fabrik AS filed Critical GEA Farmaceutisk Fabrik AS
Priority to AT86306998T priority Critical patent/ATE40888T1/de
Publication of EP0219225A1 publication Critical patent/EP0219225A1/de
Application granted granted Critical
Publication of EP0219225B1 publication Critical patent/EP0219225B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a special process for the preparation of ranitidine or acid addition salts thereof.
  • the invention also relates to an intermediate for preparing ranitidine, and a further intermediate for preparing the firstmentioned intermediate.
  • No. 1 565 966 which also describes a number of processes for the preparation of ranitidine and related compounds. These are typical analogy processes which from readily available raw materials require a series of reaction steps and cumbersome purification methods, and give low yields.
  • US patent specification No. 4 497 961 describes and claims a process for the preparation of ranitidine, consisting in reacting a thiol having the formula (A) with an alkylating agent having the formula (B) wherein L is a leaving group, preferably a halogen.
  • US patent specification No. 4 440 938 describes and claims the preparation of ranitidine by reacting a thiol (A) with an aziridine compound (ethyleneimine compound) having the formula (C)
  • GB patent specification No. 2 075 980 describes and claims the preparation of ranitidine by reacting (A) with (C); or related compounds by reacting similar compounds wherein the nitrogen atom in (A) and in (C), to which the Me groups are bonded, are otherwise substituted.
  • European patent specification No. 59 082 A1 describes the preparation of ranitidine by the reaction of 1-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]-N-methyl-2-nitroethaneamine having the formula (E) with aziridine.
  • the yield according to the examples of the application is of the order of magnitude 35-45%, the process cannot be considered suitable for industrial utilization because of the use of the extremely poisonous and cancerogenic aziridine.
  • ranitidine with the above formula (I) or an acid addition salt thereof is prepared by reacting N-[2-[[[5-(hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine having the formula (V) in an organic solvent, as for instance dimethylformamide, with dimethylamine and an N,N-(dimethylamino)triphenylphosphonium halide having the formula (VI) wherein Hal denotes bromo or chloro, after which the ranitidine thereby formed if desired is converted into an acid addition salt thereof.
  • the starting compound 5-[[(2-aminoethyl)thio]methyl]-2-furanmethanol (II) is known from US patent specification No. 4 233 302, wherein the compound is called 2-[[5-(hydroxymethyl)-2-furanyme- thyl]thio]ethaneamine.
  • the compound has not earlier been used for the preparation of ranitidine and there has not earlier been given physical data for it.
  • Example 4 D in the said application it is prepared in four steps, in small yield (21%), from furfurylmercaptan. It has now been found that the compound can be prepared in another manner and in high yield (81%) from the commercially available 5-[(dimethylamino)methyl]-2-furanmethanol as shown in the following reaction scheme
  • reaction of compound (II) with the commercially available 1,1-bis(methylthio)-2-nitroethylene (Illa) is carried out in organic solvents, preferably lower aliphatic alcohols or other lower-boiling polar solvents such as acetonitrile, whereby the compound (IV) can be obtained in a yield of 70-80%.
  • organic solvents preferably lower aliphatic alcohols or other lower-boiling polar solvents such as acetonitrile, whereby the compound (IV) can be obtained in a yield of 70-80%.
  • the reaction is preferably carried out between room temperature and the boiling point of the solvent used.
  • the subsequent reaction of the compound (IV) with methylamine proceeds at moderate temperature, preferably between 0 ° C and 100 ° C in organic solvents as for instance lower alcohols and nitriles, whereby especially ethanol, methanol and acetonitrile have proven suitable.
  • the compound (V) is obtained in a high yield (>90%) and the method is very suitable for industrial production.
  • ranitidine may be obtained as free base in high purity, or it may if desired be converted with an acid into a salt, e.g. the hydrochloride.
  • the reagent (VI) used in the reaction may be prepared in situ or in a stock solution by dissolving triphenylphosphine in an organic solvent as for instance dimethylformamide, thereafter adding chlorine or preferably bromine and finally dimethylamine in excess.
  • step (III) is suitable for industrial production and the total reaction sequence does allow the preparation of ranitidine in an overall yield of about 50%, calculated on compound (II).
  • a special advantage of the process according to the invention is that all starting materials are inexpensive, and in so far as they do not form part of the final product they may be easily regenerated (e.g. triphenylphosphine).
  • the invention also relates to the starting compound for the process according to the invention, i.e. N-[2-[[[5-(hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine of the formula (V), which is a novel compound:
  • the invention relates to the novel compound (IV), which constitutes a starting material for the compound (V), and which is N-[2-[[[5-(hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-1-methylthio-2-nitro- etheneamine of the formula
  • Triphenylphosphine (78.6 g, 300 mmol) is dissolved in dimethylformamide (300 ml). Bromine (47.0 g, 294 mmol) is added over 40 minutes at 10-14 ° C. Dimethylamine (67 g, 1.5 mol) is introduced into the resulting suspension over 30 minutes at 20-30 ° C. The resulting solution of (VI) (0.63 mmol/g) is used directly in the next step.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Furan Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (3)

1. Verfahren zur Herstellung von Ranitidin, das die Formel (I) hat
Figure imgb0021
oder von einem Säureadditionssalz davon, dadurch gekennzeichnet, dass man N-[2-[[[5-(Hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethendiamin, das die Formel (V) hat
Figure imgb0022
in einem organischen Lösungsmittel mit Dimethylamin und N,N-(Dimethylamino)triphenylphosphoniumhalo- genid, das die Formel (VI) hat
Figure imgb0023
worin Hal Brom oder Chlor bedeutet, umsetzt, wonach man das hierbei gebildete Ranitidin, falls erwünscht, in ein Säureadditionssalz davon umsetzt.
2. Chemische Verbindung, hervorragend zur Verwendung als Ausgangsmaterial im Verfahren, das in Anspruch 1 definiert ist, dadurch gekennzeichnet, dass sie N-[2-[[[5-(Hydroxymethyl)-2-fu- ranyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethendiamin ist und die Formel (V) hat.
Figure imgb0024
3. Chemische Verbindung, hervorragend zur Verwendung als Ausgangsmaterial für die Herstellung der Verbindung, die im Anspruch 2 definiert ist, dadurch gekennzeichnet, dass sie N-[2-[[[5-(Hydroxymethyl)-2-furanyl]methyl]thio]ethyl]-1-methyl-thio-2-nitroethenamin ist und die Formel (IV) hat
Figure imgb0025
EP86306998A 1985-09-27 1986-09-10 Verfahren zur Herstellung von Ranitidin oder Säureadditionssalze davon und Zwischenprodukte für diese Herstellung Expired EP0219225B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86306998T ATE40888T1 (de) 1985-09-27 1986-09-10 Verfahren zur herstellung von ranitidin oder saeureadditionssalze davon und zwischenprodukte fuer diese herstellung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK4384/85 1985-09-27
DK438485A DK153758C (da) 1985-09-27 1985-09-27 Fremgangsmåde til fremstilling af ranitidin eller syreadditionssalte deraf samt derivat af 5-((2-aminoethyl)thiomethyl)-2-furanmethanol til brug som udgangsmateriale for fremgangsmåden

Publications (2)

Publication Number Publication Date
EP0219225A1 EP0219225A1 (de) 1987-04-22
EP0219225B1 true EP0219225B1 (de) 1989-02-22

Family

ID=8133057

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86306998A Expired EP0219225B1 (de) 1985-09-27 1986-09-10 Verfahren zur Herstellung von Ranitidin oder Säureadditionssalze davon und Zwischenprodukte für diese Herstellung

Country Status (17)

Country Link
EP (1) EP0219225B1 (de)
JP (2) JPH0730063B2 (de)
KR (1) KR940003296B1 (de)
AR (1) AR241462A1 (de)
AT (1) ATE40888T1 (de)
BR (1) BR8604449A (de)
CA (1) CA1263400A (de)
DE (1) DE3662145D1 (de)
DK (2) DK153758B (de)
ES (1) ES2001804A6 (de)
FI (1) FI89596C (de)
GR (1) GR862445B (de)
IS (1) IS3148A7 (de)
MA (1) MA20777A1 (de)
NO (1) NO169650C (de)
PT (1) PT83420B (de)
SU (1) SU1531854A3 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541335A (en) * 1994-07-11 1996-07-30 Torcan Chemical Ltd. Process for preparing nizatidine
US5981757A (en) * 1998-02-02 1999-11-09 Torcan Chemical Ltd. Nizatidine preparation
CN112028862A (zh) * 2020-08-18 2020-12-04 北京云鹏鹏程医药科技有限公司 一种低ndma含量盐酸雷尼替丁的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK153841C (da) * 1980-12-30 1989-02-20 Glaxo Group Ltd Fremgangsmaade til fremstilling af ranitidin

Also Published As

Publication number Publication date
ATE40888T1 (de) 1989-03-15
NO169650C (no) 1992-07-22
FI89596C (fi) 1993-10-25
JPH07316146A (ja) 1995-12-05
KR940003296B1 (ko) 1994-04-20
JPS6272680A (ja) 1987-04-03
KR870003083A (ko) 1987-04-15
NO169650B (no) 1992-04-13
DE3662145D1 (en) 1989-03-30
EP0219225A1 (de) 1987-04-22
IS3148A7 (is) 1987-03-28
BR8604449A (pt) 1987-05-12
AR241462A1 (es) 1992-07-31
DK438485D0 (da) 1985-09-27
MA20777A1 (fr) 1987-04-01
ES2001804A6 (es) 1988-06-16
DK438485A (da) 1987-03-28
PT83420B (pt) 1989-01-17
SU1531854A3 (ru) 1989-12-23
FI863651A7 (fi) 1987-03-28
DK153758B (da) 1988-08-29
NO863735D0 (no) 1986-09-18
FI89596B (fi) 1993-07-15
JPH0730063B2 (ja) 1995-04-05
FI863651A0 (fi) 1986-09-10
GR862445B (en) 1987-01-27
JP2520376B2 (ja) 1996-07-31
PT83420A (en) 1986-10-01
NO863735L (no) 1987-03-30
CA1263400A (en) 1989-11-28
DK153758C (da) 1995-10-02

Similar Documents

Publication Publication Date Title
US4013678A (en) Process for preparing heterocyclicalkylthioalkyl-n-cyanoguanidines
EP0219225B1 (de) Verfahren zur Herstellung von Ranitidin oder Säureadditionssalze davon und Zwischenprodukte für diese Herstellung
KR0147820B1 (ko) 치환 에텐류의 제조방법
HU211774B (en) Improved process for the synthesis of n-[3-(1h-imidazol-1-yl)phenyl]-4-substituted-2-pyrimidinamines
SU1419519A3 (ru) Способ получени 1- @ 2- @ 5-(диметиламинометил)-2-(фурилметилтио)-этил @ -амино-1-метиламино-2-нитроэтилена или его гидрохлорида
WO2024079734A1 (en) Process for the preparation of substituted aminothiophene
US4908454A (en) Process of producing guanidinothiazole derivatives
US4994618A (en) Bevantolol preparation
CA2402467C (en) Method for producing heterocyclic compounds
JPH0665198A (ja) ４−クロロ−３−スルファモイル−ｎ−（２，３−ジヒドロ−２−メチル−１ｈ−インドール−１−イル）ベンズアミドを工業的に製造するための新規な方法
JPS62155268A (ja) ナイザチジンの合成法
HU193608B (en) Process for production of new dervatives of n-sulphanol-propion-amidine
NO135092B (de)
JP2767295B2 (ja) インドール―３―カルボニトリル化合物の製造方法
EP0034421B1 (de) N-Phenyl-N'-cyano-O-phenylisoharnstoffe und Verfahren zu deren Herstellung
KR810001915B1 (ko) 아미노 알킬푸란 유도체의 제조방법
HU198179B (en) Process for producing n-methyl-1-alkylthio-2-nitroethenamine derivatives
SE501162C2 (sv) Förfarande för framställning av N,N- dimetylaminometylarylföreningar
SU1384197A3 (ru) Способ получени 1- @ 2-(5-(ди-метиламинометил)-2-(фурилметилтио)-этил) @ амино-1-(метиламино)-2-нитроэтилена или его гидрохлорида и способ получени дигидрохлорида 2-(2-аминоэтил)-тиометил-5-(диметиламинометил)-фурана или его моногидрохлорида
RU2042671C1 (ru) Производное дикетен-имина в качестве промежуточного продукта для синтеза ранитидина и способ его получения
DK153757B (da) Derivat af 5-((2-aminoethyl)-thiomethyl)-2-furanmethanol
US4189444A (en) Process for the preparation of N,N'-disubstituted 2-naphthaleneethanimidamide and intermediates used therein
US20030045723A1 (en) Process for the preparation of tetrasubstituted imidazole derivatives and novel crystalline structures thereof
JPS6343382B2 (de)
JP2522931B2 (ja) 四級アンモニウム塩

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT CH DE GB LI NL SE

17P Request for examination filed

Effective date: 19870929

17Q First examination report despatched

Effective date: 19880623

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT CH DE GB LI NL SE

REF Corresponds to:

Ref document number: 40888

Country of ref document: AT

Date of ref document: 19890315

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3662145

Country of ref document: DE

Date of ref document: 19890330

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
EAL Se: european patent in force in sweden

Ref document number: 86306998.5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19960812

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19960903

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19960927

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19960930

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19961029

Year of fee payment: 11

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19970910

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19970911

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19970930

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19970930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980401

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19970910

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 19980401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19980603

EUG Se: european patent has lapsed

Ref document number: 86306998.5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20010930

Year of fee payment: 16

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20020910